Pyrimido-2&#39;-cyanine dyes



Patented June 7, 1949 PYRIMIDO-Z -CYANIN E DYES Leslie G. S. Brooker, Rochester, N. Y., and Walter F. Holcomb and Clarence Kenneth Banks, Detroit, Mich., assignors to Eastman Kodak Company, Rochester, N. Y., a corporation of New J ersey No Drawing. Application September 10, 1946, Serial No. 696,028

3 Claims.

This invention relates to new pyrimido-2-cyanine dyes prepared for use as therapeutics.

A large number of dyes of the cyanine class are known. Several of these dyes have found important uses in the field of photography, certain of th dyes acting to extend the spectral sensitivity of photographic silver halide emulsions.

We have now found that certain new compounds of the cyanine type are of particular value in the treatment of particular kinds of worm infestations. It is accordingly an object of our invention to provide new compounds useful as therapeutics. A further object is to provide a process for preparing such new compounds.

The new compounds of this invention can be represented by the following general formula:

wherein X represents an anion, e. g. chloride, bromide, iodide, p-toluenesulfonate, benzenesulfonate, methylsulfate, ethylsulfate, acetate, propionate, etc.

These compounds are of particular value in the treatment of worm infestations where the invading organism is of the class Nematoda (round worms). Among the various species of worms affected by these compounds are hookworms, ascarids, filarids and whipworms. The compounds wherein X represents chloride, benzenesulfonate, p-toluenesulfonate, methylsulfate, ethylsulfate, acetate or propionate are the more soluble compounds and the most useful thereapeutically.

To prepare the compounds formulated above, a 4,6-dimethyl-2-phenylpyrimidine methyl quaternary salt is condensed with a quinoline ethyl quaternary containing in the a-position an iodine atom or a thioether group. The condensations are advantageously effected in the presence of an acid-binding agent (basic condensing agent), e. g. a tertiary amine having an ionization constant greater than at 25 C., such as triethyl-amine, triisopropylamine, triisobutylamine, triethanolamine, N-methylpiperidine, etc., or an alkali metal carbonate, e. g. sodium or potassium carbonate. A solvent is advantageously employed as reaction medium, e. g. pyridine, quirroline, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, etc.

Typical 4,6 dimethyl 2 phenylpyrimidine methyl quaternary salts include the methiodide, the methomethylsulfate, the metho-p-toluenesulfonate, the methobenzenesulfonate, etc. These quaternary salts can be formed by the interaction of 4,6-dimethyl-Z-phenylpyrimidine and an alkyl salt, e. g. methyl iodide, dimethyl sulfate, methyl-p-toluenesulfonate, methyl benzenesulfonate, etc. employing neat if necessary.

Typical of the quinoline ethyl quaternary salts which can be employed to prepare these new compounds are: 2-iodoquinoline ethiodide, 2-iodoquinoline etho-p-toluenesulfonate, 2-iodoquino line ethoethylsulfate, Z-phenylmercaptoquinoline ethiodide (Z-phenylthioquinoline ethiodide), 2- (p tolylmercapto quinoline ethiodide, 2 (finaphthylmercapto)quinoline ethiodide, 2-(2,5- dichlorophenylmercapto) quinoline ethiodide, 2- (n-butylmercapto) quinoline ethiodide, 2-(2-benzothiazolylmercapto)quinoline ethiodide, etc. Many of these quinoline ethyl quaternary salts containing a, thioether group are described in United States Patent 2,117,936, dated May 17, 1938.

It is advantageous to prepare the iodide form of the new compounds and employ this to prepare more soluble forms, such as the chloride, the

acetate, etc.

Example 1.1'-ethz/l-3,6 dimethyl-2-phenyl- 4- pyrimido-2'-cyanine iodide 21.7 g. (1 mol.) of 4,6-dimethyl-2-phenylpyrimidine methiodide, 27.4 g. (1 mol.) of 2-iodoquinoline ethiodide, cc. of ethyl alcohol and 6.73 g. (2 mol.) of triethylamine were gently refluxed for about 30 minutes. The dye which formed was filtered off, washed on the filter first with water and then with acetone. The washed dye was twice recrystallized from methyl alcohol and obtained as reddish crystals melting "at 247 to 248 C. with decomposition. Iodine, calculated 26.38%; found 26.09%.

In a similar manner 1-ethyl-3,6-dimethyl-2- phenyli-pyrimido-Z-cyanine iodide can be prepared using an amount of 2-iodoquinoline ethop-toluenesulfonate or 2-iodoquinoline ethoethylsulfate molecularly equivalent to the 2-iodoquinoline ethiodide employed above. Using 4,6-

3 dimethyl-Z-phenylpyrimidine metho-p-toluenesulfonate and 2-iodoquinoline etho-p-toluenesulfonate, the same dye ion is obtained. Using 4,6 dimethyl-2-phenylpyrimidine metho-ptluenesulfonate and 2 -.methylmercaptoquinoline etho-p-toluenesulfonate, 1' ethyl-3,6-d'imethyl- 2 phenyl-4-pyrimido-2-cyanine-p-toluenesulfonate is obtained.

Example 2. 1'-ethyl-3,6-dimethyle2=phenylpyrimido-2-cyanine chloride Silver chloride was prepared by treating a 15 percent-solution of 340 g. of silver nitrate in distilled-water with concentrated hydrochloric acid (spwg. 1.18) until no furtherprecipitate was formed. The precipitated silver chloride was washed with water by decantation until the liquors were neutral to litmus. The washed silver chloride was filtered off and washed with .methyl alcohol.

:The-so-prepared silver chloride was added to a boi1'ing, stirredsolution of 87.5 g. of 1'-ethyl3-,6- dimethyl-2-phenyl-4-pyrimido-2-cyanine iodide in 4 Lot methyl alcohol. under reflux. The stirring and refluxing were continued for 2 to 4 hours. The solidwas then allowed to settle and then was filtered off 'by suction. The solid on the filter was washed with methyl alcohol. The filtrate and washings were concentrated to a small volume' (300to-400 cc.) on a steamhath. .The small volume was then cooled and poured into a large beaker and then diethyl ether was added until precipitation of 1'-ethyl-3,6-dimethyl-2-phenyl- 4+pyrimido-2'-cyaninechloride ceased (1200 to 1500 cc. of ether). The mixture was then chilled and-filtered by suction. The dye-chloride was dried in a steam cabinet. The dye-chloride was thus obtained reddish-orange plates melting at 247 to 248 C. with decomposition. Chloride. calculated 9.10%; found 9.08%.

Using silver. acetate instead'of silver chloride, 1' ethyl-3,6-dimethyl-2-phenyl-4-pyrimido-2'- cyanine acetate can be prepared. With silver thiocyanate, 1 thyl-3,6-dimethyl-2-phenyl-4- pyrimidmT-cyan'ine thiocyanate can be prepared. iThe dye-chloride can also be'prepared "by the following general formula:

wherein X represents an anion.

2. The new compound, prepared for use as a therapeutic, represented by the following gen- 3. The new compound, prepared for use as a therapeutic, represented by the following general formula:

on. H H t 5 6 Cz s l 1 LESLIE G. S. BROOKER. WALTER F. HOLCOMB. CLARENCE KENNETH BANKS.

REFERENCES CITED "Thefollowing references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,310,640 Kendall Feb. 9, 1943 FOREIGN PATENTS Number Country Date 425,609 Great Britain Sept. 13, 1933 

